Preparation of epothilone intermediates

• US 6,593,115 B2
• Filed: 03/19/2001
• Issued: 07/15/2003
• Est. Priority Date: 03/24/2000
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Kim, Soong-Hoon, Vite, Gregory D., Höfle, Gerhard
• Primary Examiner(s): Marx, Irene
• Application Number:
  US09/811,808
• Publication Number:
  US 20020042109A1
• Time in Patent Office: 848 Days
• Field of Search: 435/148, 435/134, 435/280, 435/135, 435/136, 435/147, 435/198
• US Class Current: 435/134
• CPC Class Codes: C07D 277/30 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C12P 17/14 Nitrogen or oxygen as hetero atom and at least one other diverse hetero ring atom in the same ring

Abstract

The present invention relates to a process for the preparation of intermediates useful in the synthesis of epothilone analogs by initially enzymatically degrading certain epothilone compounds to form ring-open structures containing a carboxyl group which is esterified, the hydroxyl groups on the moiety protected and the resulting compound oxidized by, e.g. ozone, to form a first intermediate. The first intermediate can be reacted with a triphenylphosphine adduct to yield a compound containing an ester group at position 1 which is subsequently hydrolyzed to form a second intermediate.

Claims

1. A process for preparing a compound of formula I:

wherein;

X is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl and substituted aryl;

R₁ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and heterocyclo; and

P₁ and P₂ are independently selected from the group consisting of hydrogen, aralkyl, substituted aralkyl, trialkylsilyl, triarylsilyl, dialkylarylsilyl, diarylalkylsilylalkoxyalkyl, and aralkyloxyalkyl;

comprising treating an epothilone compound of formula III or formula IV;

wherein;

R₁ is as defined above;

R₂ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo or

 

and

R₃ and R₄ are selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl and heterocyclo;

with an enzyme selected from the group consisting of chymotrypsin, pancreatin, and an esterase capable of cleaving or degrading said compound to form a compound of formula VI;

wherein R₁ and R₂ are as defined above;

optionally esterifying the carboxyl group of said compound;

optionally reacting the resulting esterified compound to form protecting groups on the hydroxyl groups of said compound; and

reacting the resulting compound with a suitable oxidizing agent to form said compound of formula I.

4. The method of claim 1, 2 or 3, wherein the esterase is pig liver esterase.

2. A process for preparing a compound of formula II:

wherein;

X is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl and substituted aryl;

R₁ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and heterocyclo;

R₂ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo or

R₃ and R₄ are selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl and heterocyclo; and

P₁, P₂, and P₃ are independently selected from the group consisting of hydrogen, aralkyl, substituted aralkyl, trialkylsilyl, triarylsilyl, dialkylarylsilyl, diarylalkylsilylalkoxyalkyl, and aralkyloxyalkyl;

comprising treating an epothilone compound of formula III or formula IV;

with an enzyme selected from the group consisting of chymotrypsin, pancreatin and an esterase capable of cleaving or degrading said compound to form a compound of formula VI;

esterifying the carboxyl group of said compound;

reacting the resulting esterified compound to form protecting groups on the hydroxyl groups of said compound;

reacting the resulting compound with a suitable oxidizing agent to form a compound of formula I;

reacting said compound with a compound of formula IX;

to form a compound of formula X;

 

and

hydrolyzing the ester group on said compound in the presence of a suitable base to form said compound of formula II.

3. A process for preparing a compound of formula I:

wherein;

X is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl and substituted aryl;

R₁ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and heterocyclo; and

each P₁ and P₂ is, independently, selected from the group consisting of hydrogen, aralkyl, substituted aralkyl, trialkylsilyl, triarylsilyl, dialkylarylsilyl, diarylalkylsilylalkoxyalkyl, and aralkyloxyalkyl;

comprising treating an epothilone compound of formula XV;

wherein;

R₁, P₁ and P₂ are as defined above;

R₂ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo or

 

and

R₃ and R₄ are selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl and heterocyclo;

with an enzyme selected from the group consisting of chymotrypsin, pancreatin and an esterase capable of cleaving or degrading said compound to form a compound of formula XVI;

wherein;

R₁, R₂, P₁ and P₂ are as defined above; and

P₃ is selected from the group consisting of hydrogen, aralkyl, substituted aralkyl, trialkylsilyl, triaryisilyl, dialkylarylsilyl, diarylalkylsilylalkoxyalkyl, and aralkyloxyalkyl;

esterifying the carboxyl group of compound of formula XVI to form an ester compound of formula XVII;

wherein X, R₁, R₂, P₁, P₂ and P₃ are as defined above;

hydrolyzing the ester compound to form a diol compound of formula XVIII;

wherein X, R₁, R₂, P₁, P₂ and P₃ are as defined above; and

reacting the diol compound with a suitable oxidizing agent to form said compound of formula I.